Salts of dextro-ascorbic acid and method of preparing same



Patented Feb. 23, 1943 OFFICE SALTS or DEXTRO-ASCORBIC ACID Ami METHOD or mnmnme SAME Simon L. Ruskin, New York, N. Y.

.No Drawing. Application October 20, 1939, Serial No. soasss Claims.

My invention relates to organic compounds of bismuth, antimony and arsenic, and more particularly to therapeutic agents consisting of or containing bismuth, antimony and arsenic compounds of dextro-ascorbic acid The treatment of syphilis, trypanosomiasis, and similar diseases, with, known compounds of bismuth, antimony and arsenic is frequently accompanied by irritation and even by definitely toxic efiects. Not uncommonly, various skin diseases, like dermatitis and gingivitis, and other affections follow the use of these metal compounds. These toxic side effects appear to be due, at least to a considerable extent, to the fact that the acid portion; of the compound is not easily compatible with or tolerated by the components of the blood stream or by the tissues, both the metal and the acid radical being quite foreign to the human organism.

It is accordingly the general object of the 'invention to provide improved therapeutic preparations of high spirochetocidal and trypanosomacidal activity which are characterized by high tissue tolerance and the absence of irritation on injection, both intramuscularly and subcutaneously. It is a further object of the invention to provide preparations of bismuth, antimony and arsenic which are distinguished by a high degree of stability, even in solution, and can be manufactured at a low cost.

I have found that the bismuth, antimony and arsenic compounds of dextro-ascorbic acid have an unusually high emciency in the treatment of syphilis and similar diseases and can be administered without pain or shock to the patient. I have found further that many patients are able to tolerate these metal compounds who do not respond satisfactorily to treatment with laevo ascorbates (cevitamates). Just why this should be so, when cevitamic acid is a normal and necessary part of the human diet and component of the human blood stream, I have not been able to determine. For patients of this type, however, the dextro-ascorbate compounds represent therapeutic agencies which are superior even to the cevitamates, and are all the more desirable because of their lower cost. The dextro-ascorbates are valuable also for patients who do not require simultaneous administration of vitamin-C values, as they represent compounds, which, as I have found by clinical investigation, are readily taken up by the blood stream and absorbed by the tissues. These comopunds are characterized by a particularly high tissue tolerance, and on administration, cause no undesirable immediate or after eifects. v I

A study of the effects of bismuth, antimony and arsenic dextro-ascorbates on patients has shown that these compounds, do, in fact, exhibit a certain, even if only moderate, vitamin-C effect which appears to be greater than can be accounted for .by the dextro-ascorbate radical itself. It may therefore be that under the influence of the metal, the dextro-ascorbate is converted in the blood stream, at least in considerable part, to the laevo ascorbate radical; or possibly the metals retard the destruction of the normal vitamin-C content of the blood.

It appears that the dextro-ascorbates owe their non-irritating and low toxic qualities to their capacity for forming protein complexes with the blood serum. This is most probably due to the specific acid radical, which is compatible with the complex substances in the blood stream. Thus the dextro-ascorbate radical appears to act as a vehicle for combining the bismuth or equivalent metal with the blood proteins to produce a complex which the tissues more readily absorb, and in this respect the new compounds provided by the present invention difier from the known compounds which, in general, are unable to form soluble compounds with the blood serum proteins and, in consequence, are quite irritating on in- Jection. I

The bismuth, antimony and arsenic dextroascorbates are themselves not readily soluble in water but can be easily brought into solution in an alkaline-medium, preferably sodium hydroxide., They may, however, also be combined with amines and other solubilizing basic inorganic and organic compounds. In any case, care should be taken that the pH of the solution is within the limits suitable for injection say, approximately 7 and preferably not above about 8.0.

My improvedtherapeutlc preparations may be marketed either in the dry form or as solutions. In the dry form, they may be composed of the 'solubilized form of the metal dextro-ascorbate,

for example, as sodium bismuth dextro-ascorbate. If desired, the bismuth dextro-ascorbate may be mixed with the necessary amount of basic material, such as sodium hydroxide or carbonate,

to produce on mixing'with a prescribed amount of water, a; solution of the sodium bismuth dextro-ascorbate of the proper pH; or free dextroascorbic acid may be mixed in the dry condition with a soluble bismuth salt and an alkaline material in proper proportions to produce, on mixing with the necessary amount of water, a solution or the complex salt. I prefer however, to prepare the solubilized dextro-ascorbates in the form of a solution, packaged in ampules containing one or more doses.

The dosage oi. the metal dextro-ascorbates described above may be equivalent, in the content oi. bismuth, antimony or arsenic, to the dosage of known anti-luetic agents containing these metals. However, because of the high efliciency of the new compounds smaller doses of the metal may be employed, thereby reducing the danger or metal poisoning. I

In place of sodium and other alkali metal compounds, also other non-toxic basic compounds can be employed such as calcium, zinc and strontium hydroxides and carbonates. If desired, the solutions can be rendered non-hemolytic by the addition of sodium chloride, sugars or other known substances employed for such purpose.

The dextro-ascorbates of the present invention may be prepared in the following manner, which is described only for purposes of illustration and as representing a preferred procedure:

Example 1.Preparation of bismuth dextroascorbate.

1.8 dextro-ascorbic acid (about .01 mol) aredissolved in 20 cc. glycerol and 10 cc. N NaOH. To this are then added under stirring and coolii: 35 cc. N NaOl-I and 22.5 cc. of aqueous Bi(NO3)5H2O (containing 2/300 moi) in the following order:

N'aOH Bi (N01) 351120 (1) cc s (2) 2.5 cc. (3) 5 cc (4) 2.5 cc. (5) 5 cc (6) 2.5 cc. (7) 5 cc -4; (8) 2.5 cc. (9) 5 cc (10) 2.5 cc. (11) 5 cc (12) 2.5 cc. (l3) 5 cc -(14) 7.5 co.

in this way the solution is always kept alkaline until the final addition of the Bi(NO3)3. The orange-colored precipitate is centrifuged, and then washed four times with distilled water by centrifugation. The moist precipitate weighing approximately 5 g. when dry (theory 5.5 g.) is suspended in 100 cc. 50% glycerol and 5N NaOl-l is dropped in under stirring until a faint cloudiness persists. The'solution is filtered through a filter cell and to the filtrate 2.5 cc. NazSOa solution (containing 250 mg.) are now added to stabilize it and it is brought down to a pH around 7.6 with excess dextro-ascorbic acid. It is then made up to 150 cc. with distilled waterand bot tied immediately. The preparation should con tain approximately 20 mg. Bi per cc.

Example 2.-Prepamtion of antimony dextroascorbate 1.8 g. dextro-ascorbic acid are dissolved in 10 cc. saturated saline (NaCl) solution. To this is added slowly under stirring 4.3 g. SbCla dissolved in 20 cc. saturated saline solution. The acid solution is cooled with ice, and under stirring and cooling 12 cc. 5N NaQI-I saturated with salt are added. This leaves the solution still acid. The precipitate is centriiuged. and is then washed three times by centriiugation with distilled water. The moist precipitate weighing 4.8 g. when dry (theory 4.9 g.) is now suspended in 100 cc. of 50% glycerol solution and 5 N alkali solution is dropped in under violent stirring until a faint permanent cloudiness remains. The solution is a filtered through anlter cell until clear. it should have "a pH around 9.6. There are then added diately. This solution should contain approximately 16 mg. Sb'per cc.

Example 3.--Preparation of arsenic dextrooscorbate 20 g. cc.) arsenious chloride are dissolved in 50 cc'. absolute alcohol and the solution shaken up with 1.8 g. dextro-ascorbic acid. Practically all the acid goes into solution which would not be the case if the arsenious chloride wereab'sent. This indicates the formation of arsenic dextroascorbate. The arsenic dextro-ascorbate is less toxic than currently used arsenic preparations in the treatment of syphilis. The pH may be adjusted with sodium hydroxide or other alkali.

The solutions of the dextro-ascorbates above described may be packaged in ampoules or if desired in the solid condition in the form of tablets. The compounds may be prepared in an indifferent atmosphere, like N2 or CO2, but this is not absolutely necessary; while if desired, the ampoules may be charged in such an atmosphere or may have CO: dissolved in the solution. 7

Various organic acids can be employed for adlusting the pH to a lower alkalinity, care being taken to avoid precipitation. Tartaric, citric, gluconic and other injectible orgahic acids may be used for this purpose. To bring the pH down .from above 9 to 8, tartaric or citric acidis satis- The bismuth, antimony and arsenic dextro-ascorbates are administered parenterally,.preferably intramuscularly. The dosage may amount to20 to 40 mg. of the metalloid once or twice weekly. They are all suitable for the treatment of syphilis and protozoan diseases, like trypanosomiasis.

In syphilis, various known arsenic and bismuth preparation will not influence the Wassermann reactionin some cases. These Wasserman fast cases responded better to'bismuth dextro-ascorbate than to known bismuth and arsenic preparations. 1

In place of NaOH, other bases may be employed, such as KOH, Na2CO3, etc., while in place of dextro-ascorbic acid and a base, a salt of dextro-ascorbic acid maybe used. The inorganic salts of bismuth, antimony and arsenic above named may be replaced by other salts having relatively non-toxic anions and capable of entering into double decomposition with dextro-ascorbates; if desired, the hydroxides of the metalloids may be used, but they generally react with dextro-ascorbic acid only with difliculty. .The sodium sulphite may be used with or be substituted by citrates, sucrose, organic acids like tartaric and citric acids, or other stabilizers which are suitable Iorinjection.

The dextro-ascorbate salts of the present invention are quite stable toward heat, sterilization and toward oxidation, considerably more so. than the corresponding laevo ascorbate compounds. Not only inorganic but also organic compounds of the metalloids can be employed. Thus in the case of arsenic, the phenyl arsene oxscribed above may be resorted to within the scope of the appended claims without departing from the spirit of the invention.

Thus, calcium-hydroxide may be employed in place of sodium hydroxide to bring the dextroascorbate compounds of bismuth and antimony into solution, thereby producing the calcium-bismuth complex which serves at the same time to correct any calcium deficiency from which the patient may be sufiering. If desired, the alkalinity of the solution of, for example, the sodiumbismuth or the calcium-bismuth complexmay be reduced by the addition of cevitamic acid, or of any other organic acid suitable for injection, such as citric, gluconic, lactic and the like. Also, instead of bringing, for example, the bismuth, dextro-ascorbate into solution with the aid of an alkaline material, it may be injected in the form of a suspension, either in water or any other medium employed for injection,such as sesame oil, glycerlne and the like.

I claim:

1. A solubilized compound of dextro ascorbic acid and an element of the group consisting of arsenic, antimony and bismuth.

2. A soluble derivative of bismuth dextro-ascorbate. a

3. A sodium dextro-ascorbate of an element of the group consisting of arsenic, antimony and bismuth.

4. Sodium bismuth dextro-ascorbate.

5. Calcium bismuth dextro-ascorbate.

6. As a therapeutic agent, a non-hemolytic so lution of a compound of an element of the group consistingof arsenic, antimony, and bismuth, and dextro-ascorbic acid.

7. A therapeutic preparation containing a dextro-ascorbic acid compound of an element of the group consisting of arsenic, antimony and bis- 8. A therapeutic preparation comprising the reaction product of dextro-ascorbic acid, an element of the group consisting of arsenic, antimony and bismuth, and a base.

' valuable compound or an element of the group consisting of arsenic, antimony and bismuth, which comprises dissolving dextro-ascorbic acid in glycerol, adding a, quantity of a sodium base insufllcient to neutralize the acid, and then add-' ing an aqueous solution of a soluble inorganic salt or such-element in an amount approximately equivalent to the dextro-ascorbic acid and a fur ther quantity of sodium base suflicient to yield a 

